1. Field of the Invention
This invention relates to new derivatives of camptothecin, an alkaloid possessing anti-tumor activity (including carcinostatic activity), and to processes for preparation of such derivatives. More particularly, this invention relates to new camptothecin derivatives bearing hydroxy or a functionally converted hydroxy substituent in the 5-position or an organic carbon substituent in the 7-position thereof and possessing at least one of strong anti-tumor activity and low toxicity as well as processes for the preparation of such derivatives.
2. Description of the Prior Arts
Camptothecin is a cytotoxic alkaloid, isolated first by Wall and his co-workers [J.Am. Chem. Soc. 88(1966), 3888] from leaves and barks of Camptotheca accuminata (NYSSACEAE), a plant native to China, which has a pentacyclic structure consisting of a fused ring system of quinoline (rings A and B), pyrroline (ring C), .alpha.-pyridone (ring D) and a six-membered lactone (ring E) and displays dextro-rotation due to the S-configuration of a tertiary hydroxy group in the 20-position. Earlier reports on the carcinostatic activity of camptothecin based on inhibitory activity toward an experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 tumor in rats [Chem. Rev. 23(1973), 385; Cancer Treat. Rep., 60(1967), 1007] stimulated synthetical researches on camptothecin, but the subsequent biological evaluation in the reports indicated that this compound is highly toxic and consequently unusable as a chemotherapeutic agent. Because of high toxicity, camptothecin itself is not utilized at present for clinical treatments except in China, but this compound is still one of the most potent substances with antitumor activity and is thus regarded as important in the aspect of a biological reagent capable of inhibiting selectively the biosynthesis of ribosomal and messenger RNA's without disturbing the biosynthesis of mitochondrial, 4S or 5S RNA's [Nature (London), New Biol., 237(1972), 144].
Such earlier reports on the significant antitumor activity of camptothecin stimulated intensive interest in the total syntheses and chemical modifications of camptothecin. Many papers describe the syntheses of dl-camptothecin, its intermediate derivatives, and (+)-20(S)-camptothecin; synthesis of (+)-20(S)-camptothecin (Dextro-rotary) is reported by E. J. Corey et al., in J. Am. Chem. Soc. 40 2140 (1975). In addition, synthesis of dl-camptothecin is reported, for example, by J. C. Bradley et al., in J. Org. Chem. 41,699(1976) and by H. G. M. Walraven et al., in Tetrahedron 36, 321 (1980), the latter being a report on the latest synthesis of camptothecin. The natural camptothecin isolated from Camptotheca accuminata is known to be in the d-form. However, none of these reports refer to chemical modification of the original structure of camptothecin from the standpoint of chemotherapeutic usage. The chemical modifications so far reported are mainly concerned with the rings D and/or E of camptothecin, but the results of such modifications have revealed only failure in maintaining expected carcinostatic activity and poor improvement in toxicity [J. Med. Chem., 19(1976), 675] .
From the chemotherapeutic point of view, it is of importance that the chemical modifications of camptothecin should be restricted in the rings A, B and C without effecting any serious change in the whole skeletal structure, especially in the rings D and E of the natural camptothecin, the latter rings D and E being conceivable to be one of the essential structural elements for the expression of the above mentioned biological activity. Functionalization of a moiety containing the rings A, B and C is little known, except for nitration of camptothecin in concentrated sulfuric acid under severe conditions conducted in China to obtain 12-nitrocamptothecin after troublesome separation treatments from other products. This 12-nitro derivative is then reduced to the corresponding 12-amino derivative which is further subjected to diazotization and subsequent hydrolysis or a Sandmeyer reaction to introduce a hydroxy group, chlorine atom, cyano group or carboxyl group into the 12-position of camptothecin [P. Pei-chuang et al.; Hau Hsueh Hsueh Pao, 33 (1975), 71; Chem. Abstr., 84 (1976), 115629p]. According to this method, however, it takes four steps to prepare the 12-cyano derivative and five steps to prepare the 12-carboxy derivative from the starting natural camptothecin. Except for this method wherein a number of troublesome steps are required for introducing a functional substituent into the 12-position of camptothecin, there has not yet been known heretofore any chemical modification for introducing a functional substituent in the ring A, B and/or C. The reason why introduction of a substituent into the ring A, B and/or C of camptothecin is extremely difficult is probably ascribable to poor solubility of camptothecin in ordinary organic solvents and to the nature of a nitrogen-containing heterocyclic ring which refuses an ionic reaction, especially the so-called electrophilic reaction conventionally carried out on aromatic rings, such as the Friedel-Crafts reaction, Vilsmeier-Haack reaction or other alkylation or acylation reactions.
Thus, there is still a great demand in this art for developing new derivatives of camptothecin possessing at least one of high anti-tumor activity and very weak toxicity by chemically modifying natural camptothecin on its ring A, B and/or C in one step without effecting any change in the structure of the rings D and E which are regarded to be indispensable for exhibiting the physiological activity.